Angiogenesis is the formation of new blood vessels from pre-existing vasculature and may be controlled by intricate signalling via soluble factors. Pathologies associated with angiogenesis may include cancer (Folkman J. (1971) N. Engl. J. Med. 285:1182; Folkman J. (1999) Nature Med. 1: 27-31), arteriosclerosis (Lip, G. Y., Blann, A. D. (2004) Ann Med. 36(2) 119-125), psoriasis (Powell, J. (1999) Curr. Opin. Pediatr. 11: 457-463), endometriosis (Olive, D. L., Lindheim, S. R., Pritts, E. A. (2004) Best Pract. Res. Clinc. Obstet. Gynaecol. 18(2) 319-328) and some ocular disorders like diabetic retinopathy (Folkman J. (1999) Nature Med. 1: 27-31). Angiogenesis may also be necessary for wound repair since the new vessels provide nutrients to support the active cells, promote granulation tissue formation and facilitate the clearance of debris. Approximately 60% of the granulation tissue mass may be composed of blood vessels which also supply the necessary oxygen to stimulate repair and vessel growth. It is well documented that angiogenic factors are present in wound fluid and promote repair while antiangiogenic factors inhibit repair. In tumors, when endothelial cells are exposed to soluble factors which stimulate angiogenesis, they may undergo several physiological changes including a massive increase in proliferation, degradation and invasion through the existing vessel basement membrane, and migration away from the blood vessel to a new location. At the new location the endothelial cells may again proliferate and form capillary tubules before ultimately forming a highly disorganised tumor vasculature (Garcea G, Lloyd T D, Gescher A, Dennison A R, Steward W P, Berry D P. (2004) Eur J. Cancer. June; 4099):1302-13). Activated endothelial cells may show a distinct pattern of gene expression, which leads to modification of the principal cellular functions involved in angiogenesis. These include the regulation of proteolytic balance leading to localised pericellular matrix degradation, synthesis of adhesion molecules involved in extracellular matrix interaction, and most importantly, cytoskeletal reorganization involved in cell migration (Garcea G, Lloyd T D, Gescher A, Dennison A R, Steward W P, Berry D P. (2004) Eur J. Cancer. June; 4099):1302-13).
Novel anti-angiogenic compounds have been shown to inhibit a range of endothelial markers, which have been identified as being up-regulated in activated endothelial cells. These may include receptors, matrix metalloproteins, and adhesion proteins. The success rate of these inhibitors has been quite high. Recently the novel anti-angiogenic compound Avastin, a VEGF antibody, has passed FDA approval and anti-angiogenesis has now become recognised as the fourth modality used in the treatment of cancer (Abdollhi. A., Hlatky L., Huber P. E. (2005) Drug Resistance Updates, February-April; 8:59-74). These therapies may have the following advantages over conventional chemotherapeutic treatments. First, angiogenesis is primarily an onco-foetal mechanism, thus minimal side effects should be expected when administered, even after prolonged treatment. Secondly, tumor-associated angiogenesis is a physiological host mechanism and its pharmacological inhibition should, consequently, not lead to the development of resistance. Finally the tumor mass itself is difficult to target, where the endothelial cells that line the supplying vasculature are frequently classed as vulnerable.
Pro-angiogenic compounds may also be therapeutic. For example, pro-angiogeneic compounds which may promote wound repair include angiogenic cytokines, such as FGF, VEGF, TGF-beta, angiopoietin, and mast cell tryptase.
A novel polypeptide and its gene have been recently identified and partially characterised. This new polypeptide has been named FKBP-L, DIR1 or WISP39. This gene has been demonstrated as having a role in stress responses (Robson, T., Lohrer, H., Bailie, J. R., Hirst, D. G., Joiner, M. C., Arrand, J. E. (1997) Biochemical J. Transactions 25, 335-341). It has also been shown that repression of the FKBP-L gene can protect against cellular X-ray and UV-induced oxidative cellular damage (Robson, T., Joiner, M. C., McCullough, W., Price, M. E., McKeown, S. R., Hirst, D. G. (1999) Radiation Research 152, 451-461; Robson, T., Price, M. E., Moore, M. L., Joiner, M. C., McKelvey-Martin, V. J., McKeown, S. R., Hirst, D. G., (2000) Int. J. Radiat). FKBP-L may also stabilize newly synthesised p21 (a cyclin dependent kinase inhibitor and a critical regulator of cell cycle) by forming a trimeric complex with p21 and Hsp90 (Jascur, T. et al (2005) Molecular Cell, Vol. 17, 237-249).
There is a need to provide new therapeutics that can modulate angiogeneis and cell migration. Such therapeutics may be important as stand-alone treatments, or to be used in conjunction with other therapeutic agents.